Is COL2A1 p.Val983Ile (c.2947G>A) pathogenic?

COL2A1 p.Val983Ile (c.2947G>A) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-06). AlphaMissense: likely benign (0.1767); Ultra-rare (popmax 0.0117%, amr); Associated with multiple epiphyseal dysplasia, Beighton type.

What condition is associated with COL2A1 p.Val983Ile (c.2947G>A)?

COL2A1 p.Val983Ile (c.2947G>A) is associated with multiple epiphyseal dysplasia, Beighton type, Stickler syndrome type 1, Legg-Calve-Perthes disease (ClinVar).

How common is COL2A1 p.Val983Ile (c.2947G>A) in the general population?

COL2A1 p.Val983Ile (c.2947G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about COL2A1 p.Val983Ile (c.2947G>A)?

AlphaMissense predicts likely benign (score 0.1767) — an in-silico prediction, not a clinical call.

COL2A1 p.Val983Ile

c.2947G>A · rs772889503 · VCV1011511

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1767 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

multiple epiphyseal dysplasia, Beighton type

Computational evidence

Protein change
AlphaMissense	0.1767	likely benign
REVEL	0.498	indeterminate
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,002 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000805% 13/1,613,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,572
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.0022%	45,544
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000169%	590,016

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COL2A1
Protein: p.Val983Ile
Coding: c.2947G>A
MANE Select: NM_001844
dbSNP: rs772889503
Type: single nucleotide variant
Location: chr12:47978347 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 983: the 'disordered' region; the 'triple-helical region' region

Full COL2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multiple epiphyseal dysplasia, Beighton type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Stickler syndrome type 1 Legg-Calve-Perthes disease platyspondylic dysplasia, Torrance type Kniest dysplasia spondyloepiphyseal dysplasia congenita spondyloepimetaphyseal dysplasia, Strudwick type achondrogenesis type II spondyloperipheral dysplasia mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis spondyloepiphyseal dysplasia with metatarsal shortening Stickler syndrome, type I, nonsyndromic ocular spondyloepiphyseal dysplasia, Stanescu type vitreoretinopathy with phalangeal epiphyseal dysplasia avascular necrosis of femoral head, primary, 1

Similar variants

COL2A1 p.Val983= Conflicting classifications of pathogenicity ★ same residue
COL2A1 c.1222-2A>G Pathogenic ★★ same condition
COL2A1 c.1365+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1420-1G>A Pathogenic ★★ same condition
COL2A1 c.1420-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1527+135G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1527+1G>A Likely pathogenic ★★ same condition
COL2A1 c.1581+1G>A Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/col2a1-p-val983ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown